FET Fusion Oncoproteins Disrupt Physiologic DNA Repair and Create a Targetable Opportunity for ATR Inhibitor Therapy

In cancers with genetic loss of specific DNA damage response (DDR) genes (e.g., BRCA1/2 tumor-suppressor mutations), synthetic lethal targeting of compensatory DDR pathways has translated into clinical benefit for patients. Native FET family members are among the earliest factors recruited to DNA double-strand breaks (DSB), and FET fusion oncoproteins drive a diversity of sarcomas and leukemias. A better understanding of both native FET protein and FET fusion oncoprotein function in DNA repair could reveal tumor-specific vulnerabilities and provide therapeutic opportunities. In this study, we focus on Ewing sarcoma, a pediatric bone tumor driven by the FET fusion oncoprotein EWSR1::FLI1, as a model for FET-rearranged cancers. We discovered that recruitment of EWSR1::FLI1 and other FET fusion oncoproteins to DNA DSBs impairs the activation and downstream signaling of the DNA damage sensor ATM. The compensatory ATR signaling axis acts as a collateral dependency and therapeutic target in patient-derived xenograft models of multiple FET-rearranged cancers. In summary, these findings describe how oncogenes can disrupt physiologic DNA repair and provide the preclinical rationale for testing ATR inhibitors in FET-rearranged cancers as part of ongoing early-phase clinical trials. Significance: FET fusion oncoproteins subvert genome maintenance by impairing ATM activity, bridging two key fields-oncogene biology and DNA repair-and proposing ATR inhibition as a targeted therapeutic approach for FET rearranged cancers.